2-Amino-1,4-dihydropyridine derivatives

ABSTRACT

2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

Meyer et a1.

Z-AMINO- 1 ,4-DIHYDROPYRIDINE DERIVATIVES Inventors: Horst Meyer;Friedrich Bossert,

both of Wuppertal-Elberfeld; Wulf Vater, Opladen; Kurt Stoepel,Wuppertal-Elberfeld, all of Germany Assignee: Bayer Aktiengesellschaft,Germany Filed: Mar. 27, 1974 Appl. No.: 455,306

Related U.S. Application Data Division of Ser. No. 336,639, Feb. 28,1973, Pat. No. 3,867,393.

Foreign Application Priority Data Mar. 6, 1972 Germany 2210674 U.S. Cl...260/294.8F; 260/256.4R; 256.4 260/287 R; 260/289 R; 260/294.8 C;260/294.8 D; 260/294.8 G; 260/295 R; 260/295.5 R; 260/296 R; 424/251;424/258; 424/266 Int. Cl. C07D 213/50 Field of Search 260/294.8 G, 294.8F, 294.9, 260/295.5 R, 296 R NOV. 4, 1975 [56] References Cited UNITEDSTATES PATENTS 3,775,422 11/1973 Bossert et al. 260/294.9 3,799,9343/1974 Meyer et a1 260/295.5 R 3,799,936 3/1974 Meyer et a] 260/295.5 R

Primary Examiner-Alan L. Rotman [57] ABSTRACT2-Amino-1,4-dihydropyridines bearing a carbonyl function in the5-position and being optionally substituted by lower alkyl or phenyl inthe 6-position, and the corresponding 2-amino-1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonylgroup in. the 3-position and optionally substituted in the 4-position bylower alkyl, phenyl, substituted phenyl or a heterocyclic group areantihypertensive agents and coronary vessel dilators. The compounds, ofwhich 2-amino-6-methyl-4-(3- nitrophenyl 1 ,4-dihydropyridine-3 ,5-dicarboxylic acid 3,5-diethyl ester is a representative embodiment, areprepared through condensation of an ylideneacetoacetic acid ester and anamidine.

4 Claims, N0 lDrawings 2-AMINO-1,4-DIHYDROPYR1DINE DERIVATIVES This is adivision of application Ser. No. 336,639 filed Feb. 28, 1973, now US.Pat. No. 3,867,393.

DETAILED DESCRIPTION The present invention pertains to2-amino-l,4-dihydropyridine derivatives, to processes for theirproduction and use and to pharmaceutical compositions containing suchcompounds and useful as antihypertensive agents and coronary vesseldilators.

In particular, the present invention pertains to compounds of theformula wherein R is hydrogen; lower alkyl; lower alkenyl; loweralkynyl; phenyl; substituted phenyl in which the substituents are one tothree members selected from the group consisting of lower alkyl, loweralkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(loweralkoxy), lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio orphenyl; naphthyl; or a heterocyclic ring selected from the groupconsisting of quinolyl, isoquinolyl, pyridyl, pyrimidyl, thenyl, furyland pyrryl, said heterocyclic ring being unsubstituted or substituted byone or two members selected from the group consisting of lower alkyl,lower alkoxy and halogeno;

R when taken independently, is hydrogen, lower alkyl, phenyl or pyridyl;

R when taken independently, is lower alkyl, lower alkoxy, loweralkoxy(lower alkoxy), lower alkenyloxy, lower alkynyloxy, amino, loweralkylamino or di(lower alkyl)amino,

R and R when taken together are alkylene of two to four carbon atoms;and

R is lower alkyl, lower alkoxy, lower alkoxy(lower alkoxy), loweralkenyloxy, lower alkynyloxy, amino, lower alkylamino or di(lower alkyl)amino.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from one to six carbon atoms.Representative of such lower alkyl groups are thus methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl,isopentyl, neopentyl, tert.pentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from two to six carbon atoms andnonterminal ethylenic unsaturation as, for example, vinyl, allyl,isopropenyl, Z-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl,Z-hexenyl, 4-hexenyl, and the like.

The term lower alkynyl denotes a univalent branched or straighthydrocarbon chain containing from two to six carbon atoms andnonterminal acetylenic unsaturation as, for example, ethynyl,2-propynyl, 4-pentynyl, and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through an ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbonchain bound to the remainder of the molecule through a divalent sulfuras, for example, methylthio, ethylthio, propylthio, isopropylthio,butylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to the physiologicallyacceptable non-toxic acid addition salts of these basic compounds. Suchsalts include those derived from organic and inorganic acids such as,without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, embonic acid,enanthic acid, and the like.

According to the present invention, the foregoing compounds are preparedby reacting a dicarbonyl compound of the formula:

COR

RC H=C coR wherein R, R and R are as herein defined, with an am idine ofthe formula:

in which R is as herein defined. The condensation proceeds smoothly ingood yields simply by heating the two components, generally in thepresence of an inert organic solvent such as methanol, ethanol, propanoland similar alkanols, ethers such as dioxane and diethyl ether, glacialacetic acid, pyridine, dimethylformamide, dimethylsulfoxide,acetonitrile and the like. The reaction is conducted at temperatures offrom 20 to 250C, conveniently at the boiling point of the solvent, andwhile elevated pressure may be utilized, normal atmospheric pressure isgenerally satisfactory. The reactants are employed in substantiallyequimolar amounts. The amidine reactant can be employed as the free baseor in the form of a salt such as the hydrohalide salts with the amidinebeing liberated from the salt through treatment with a basic agent suchas an alkali metal alkox ide. The dicarbonyl reagent can be utilized assuch or generated in situ by the reaction of an aldehyde of the formulaRCI-IO and a B-dicar'bonyl compound of the formula RCOCI-I COR It israther surprising that the above described condensation produces thedesired compounds in such good yields and with such high purity forwhile it is known that a benzylideneacetoacetic acid ester can becondensed with an amino crotonic acid ester to yield al,4-dihydropyridine (Knoeve-nagel, Ber. 31, 743, 1898), it would beexpected from. for example, Silver smith, J. Org. Chem. 27, 4090 (1952)that the addition of an amidine to an a,fi-unsa'turated keto compoundwould yield the dihydropyrimidine derivative rather than thedihydropyridine derivative.

Many of the dicarbonyl compounds utilized as one of the reactants areknown to the art and the others can either be generated in situ asherein described or prepared according to methods well known to the art,see for example Org. Reaction XV, 204 et seq. (1967). Typical of thisreactant are the following compounds:

benzylideneacetoacetic acid methyl ester,

ethylideneacetoacetic acid methyl ester, isopropylideneacetoacetic acidmethyl ester, 2-nitrobenzylideneacetoacetic acid methyl ester,2-nitrobenzylideneacetylacetone, benzylideneacetylacetone,3-nitrobenzylideneacetoacetic acid methyl ester,3-nitrobenzylideneacetoacetic acid propargyl ester,3-nitrobenzylideneacetoacetic acid allyl ester,3-nitrobenzylideneacetoacetic acid B-methoxyethyl ester,

3-nitrobenzylideneacetoacetic acid B-ethoxyethyl ester,

3-nitrobenzylideneacetoacetic acid isopropyl ester,

3-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetylacetone, 4-nitrobenzylideneacetoacetic acidB-propoxyethyl ester,

4-nitrobenzylideneacetoacetic acid n-propyl ester,

3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid ethyl ester,

2-cyanobenzylidenepropionylacetic acid ethyl ester,

3-cyanobenzylideneacetoacetic acid methyl ester,

3-nitro-4-chlorobenzylideneacetylacetone,

3-nitro-4-chlorobenzylideneacetoacetic acid t-butyl ester,

3-nitro-4-chlorobenzylideneacetoacetic acid methyl ester,2-nitro-4-methoxybenzylideneacetoacetic methyl ester,2-cyan0-4-methylbenzylideneacetoacetic acid ethyl ester,

2-azidobenzylideneacetoacetic acid ethyl ester,

3-azidobenzylideneacetylacetone,

2-methylmercaptobenzylideneacetoacetic acid isopropyl ester,

2-sulphinylmethylbenzylideneacetoacetic acid ethyl ester,

2-sulphonylbenzylidenemethylacetoacetic acid allyl ester,

4-sulphony[methylbenzylideneacetoacetic acid ethyl ester,

naphth-l-ylideneacetoacetic acid methyl ester,

naphth-l-ylideneacetoacetic acid ethyl ester,

naphth-2-ylideneacetoacetic acid ethyl ester,

Z-ethoxynaphthl-ylideneacetoacetic acid methyl ester,

2-meth0xynaphth-l-ylideneacetoacetic acid ethyl ester,

S-bromonaphth-l-ylideneacetoacetic acid methyl ester,

quinol-2-ylmethylideneacetoacetic acid methyl ester,

quinol-3-ylmethylideneacetoacetic acid methyl ester,

quinol-4-ylmethylideneacetoacetic acid ethyl ester,

quinol-8-ylmethylideneacetoacetic acid ethyl ester.

isoquinol-l-ylmethylideneacetoacetic acid methyl ester,

acid

isoquinol-3-ylmethylideneacetoacetic acid methyl ester,

oz-pyridylmethylideneacetoacetic acid methyl ester,

oz-pyridylmethylideneacetoacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid allyl ester,

a-pyridylmethylideneacetoacetic acid cyclohexyl ester,

,B-pyridylmethylideneacetoacetic yethyl ester,

y-pyridylmethylideneacetoacetic acid methyl ester,

-methyl-a-pyridylmethylideneacetoacetic acid ethyl ester,

4,6-dimethoxypyrimid-5-ylmethylideneacetoacetic acid ethyl ester,

then-2-ylmethylideneacetoacetic acid ethyl ester,

fur-2-ylmethylideneacetoacetic acid allyl ester,

pyrr-Z-ylthylideneacetoacetic acid methyl ester,

nitrobenzylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid ethyl ester,

oz-pyridylmflhylidenepropionylacetic acid methyl ester,

oz-pyridylmethylideneacetylacetone,

2-, 3- or 4-methoxybenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-methoxybenzylideneacetylacetone,

2-methoxybenzylideneacetoacetic acid allyl ester,

Z-methoxybenzylideneacetoacetic acid allyl ester,

2-methoxybenzylideneacetoacetic acid propargyl ester,

2-meth0xybenzylideneacetoacetic acid B-methoxyethyl ester,

2-isopropoxybenzylideneacetoacetic acid ethyl ester,

3-butoxybenzylideneacetoacetic acid methyl ester,

3,4,5-trimeth0xybenzylideneacetoacetic acid allyl ester,

Z-methylbenzylidenepropionylacetic acid methyl ester,

2. 3- or 4-methylbenzylideneacetoacetic acid ethyl ester,

Z-methylbenzylideneacetoacetic yethyl ester,

2-methylbenzylideneacetoacetic acid ,B-propoxyethyl ester,

2-methylbenzylideneacetylacetone,

3,4-dimethoxy-5-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-chlorobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-fluorobenzylideneacetoacetic acid ethyl ester,

2-fluorobenzylideneacetoacetic acid methyl ester,

3-chlorobenzylideneacetylacetone.

3chlorobenzylidenepropionylacetic acid ethyl ester.

3-chlorobenzylideneacetoacetic acid ethyl ester,

2-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3- or 4-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3-trifluoromethylbenzylideneacetoacetic acid methyl ester,

Z-carbethoxybenzylideneacetoacetic acid methyl ester,

3-carbomethoxybenzylideneacetoacetic acid methyl ester,

4-carboisapropoxybenzylideneacetoacetic acid isopropyl ester.

acid ,B-methoxacid B-methox- 4-carbomethoxybenzylideneacetoacetic acidallyl ester,

3-nitrobenzylidenecyclohexanel ,3-dione, and

3-nitrobenzylidenecycloheptane-l ,3-dione.

The amidine reactants are similarly known or can be readily producedaccording to known methods, see for example McElvain et al., J.A.C.S.,73, 2760 (1951). Typical of these reactants are the following:

amidinoacetic acid methyl ester,

amidinoacetic acid ethyl ester,

amidinoacetic acid n-propyl ester,

amidinoacetic acid isopropyl ester,

amidinoacetic acid cyclohexyl ester,

amidinoacetic acid B-methoxyethyl ester,

amidinoacetic acid a-ethoxyethyl ester,

amidinoacetic acid B-ethoxyethyl ester, amidinoacetic acid propargylester, and amidinoacetamide.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a dis tinct and long lastingdilation of the coronary vessels which is intensified by a simultaneousnitrite-like effect of reducing the load on the heart. The effect onheart metabolism is thus one of energy saving. in addition, thecompounds lower the 'blood pressure of normotonic and hypertonic animalsand can thus be used as antihypertensive agents. These properties can beconveniently observed in well known laboratory models. Thus for examplethe coronary vessel dilation effect can be observed by measuring theincrease in oxygen saturation in the coronary sinus in the narcotized,heart catheterized dog, as shown in the following table:

l.V. Dose (mg/kg) Return to normal 0 values (hours) Compound saturationThe hypotensive activity of the present compounds can be observed bymeasuring the blood pressure of hypertensive rats followingadministration of the compounds. The following table demonstrates thedose which results in at least a mm Hg reduction in blood pressure ofsuch animals:

Compound Dose (mg/kg) Z-amino-6-meth 'l 4-phenyll .4- 1.0dihydropyridined.5-dicarboxylic acid diethyl ester 2-amino-6meth\'l--1-(.lnitrophenyll' l.4-dihydropyridine-3.5-dicarboxylic acid 3-eth\l ester 5-meth \'l ester -continued Compound Dose (mg/kg) The toxicityof the compounds is remarkably low. Thus for example the toxic dose of2-amino-6-methyl- 4-( 2-trifluoromethylphenyl )-l,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester in mice uponoral administration is greater than 1,000 mg/kg.

In addition to the effect on blood pressure and coronary vessels, thecompounds also lower the excitability of the stimulus formation andexcitation conduction system within the heart so that anantifibrillationaction is observed at, therapeutic doses. The tone of the smooth muscleof the vessels is also greatly reduced. This vascular-spasmolytic actioncan be observed in the entire vascular system as well as in more or lessisolated and circumscribed vascular regions such as the central nervoussystem. In addition, a strong muscular-spasmolytic action is manifestedin the smooth muscle of the stomach, the intestinal tract, theurogenital tract and the respiratory system. Finally, there is someevidence that the compounds influence the cholesterol level and lipidlevel of the blood. These effects complement one another and thecompounds are thus highly desirable as pharmaceutical agents to be usedin the treatment of hypertension and conditions characterized by aconstriction of the coronary blood vessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from to 0.5%, of at least one2-amino-l,4-dihydropyridine as herein defined in combination with apharmaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which isnontoxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e., physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three four or more single doses or, altematively,one-half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole. half,third or quarter of the daily dosage administered once, twice, three offour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness. generally the daily dose will befrom about 0.001 to about 2 mg/kg, preferably 0.005 to 1.0 mg/kg, whenadministered parenterally and from about 0.1 to about mg/kg, preferably0.5 to 10 mg/kg, when administered orally. In some instances asufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acacia mucilage or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly fonned slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themidicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared'indosage unit form so that a given quantity contains a predeterminedamount of the compound.

Syrups can be prepared by dissolving the compound in a suitably flavoredaqueous sucrose solution while elixers are prepared through the use of anontoxic alcoholic vehicle..Suspensions can be formulated by dispersingthe compound in a nontoxic vehicle. Solubilizers and emulsifiers such asethoxylated isostearyl alco- 8 hols and polyoxyethylene sorbitol esters,preservatives, flavor additives such as peppermint oil or saccharin, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These examples should not be construed as a limitation on the scope ofApplicants invention since the subject matter regarded as the inventionis set forth in the appended claims.

EXAMPLE 1 Upon boiling a solution of 21.8 g of benzylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 2 hours,2-amino-6-methyl-4-phenyl-l,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 164C (alcohol) is obtained. Yield: 67% oftheory.

EXAMPLE 2 Upon boiling a solution of 24.9 g of2-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester 5- methyl ester of melting point 168C (alcohol) isobtained. Yield: 59% of theory.

EXAMPLE 3 Upon boiling a solution of 24.8 g of2-methoxybenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in ml of ethanol for 1 hour,2-amino-6-methyl-4-( Z-methoxyphenyl )-1 ,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point170C (ethanol) is obtained. Yield: 65% of theory.

EXAMPLE 4 Upon boiling a solution of 23.2 g ofZ-methylbenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours,2-amino-6-methyl-4-( 2-methylphenyl l ,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point130C (ethanol) is obtained. Yield: 71% of theory.

EXAMPLE EXAMPLE 6 Upon boiling a solution of 14.2 g of2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour.2-amino-6-methyl-4'(2-trifluoromethylphenyl)-l,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 156C (ethanol) is obtained. Yield 76% oftheory.

EXAMPLE 7 Upon boiling a solution of 12.6 g of3-chlorobenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methyl-4-( 3-ch1o rophenyl)- 1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 157159C (ethanol) is obtained. Yield: 62% of theory.

EXAMPLE 8 Upon boiling a solution of 13.2 g of4-methylmercaptobenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl-4-(4-methylmercaptophenyl)-l,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 165C (ethyl acetate/petroleum ether)is obtained. Yield 49% of theory.

EXAMPLE 9 Upon boiling a solution of 26.3 g of3-nitrobenzylideneacetoacetic acid ethyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 200 ml of ethanol for 1 hour,2-amino-6-methyl-4-( 3-nitrophenyl)-1 ,4-dihydropyridine3,5-dicarboxylic acid diethyl ester of melting point 169C (ethanol) isobtained. Yield: 58%- of theory.

EXAMPLE 10 Upon boiling a solution of 24.9 g of3-nitrobenzylideneacetoacetic acid methyl ester and 13.0 g ofamidinoacetic acid ethyl ester in 180 ml of ethanol for 1 hour,2-amino6-methyl-4-( 3-nitrophenyl)- l ,4-dihydropyridine3,5-dicarboxylicacid 3-ethyl ester 5- methyl ester of melting point 124C is obtained.Yield: 59% of theory.

EXAMPLE 1 1 Upon heating a solution of 13.8 g of3-nitrobenzylideneacetoacetic acid isopropyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-nitrophenyl)-1 ,4-dihydropyridine-3,S-dicarboxylicacid 3-ethyl 5-isopropyl ester of melting point 206 207C (alcohol) isobtained. Yield: 62% of theory.

EXAMPLE 12 Boiling a solution of 10.9 g of 3-nitrobenzylideneacetoaceticacid propargyl ester and 5.2 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 10' 1 hour yields2'amino-6-methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylicacid 3-ethyl ester 5- propargyl ester of melting point 181C (ethanol).Yield: 59% of theory.

EXAMPLE 13 Heating a solution of 14.6 g of 3-nitrobenzylideneacetoaceticacid B-methoxyethyl ester and 6.5 g of amidinoacetic acid ethyl ester in150 ml of ethanol for 1 hour yields 2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl esterS-fi-methoxyethyl ester of melting point 179C (ethyl acetate/petroleumether). Yield: 58% of theory.

EXAMPLE 14 Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.0g of acetylacetone and 6.5 of amidinoacetic acid ethyl ester in ml ofethanol for 2 hours, 2- amino-5-acetyl-6-methyl-4-( 3-nitrophenyl 1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 217C(ethanol) is obtained. Yield: 48% of theory.

EXAMPLE 15 Upon boiling a solution of 14.2 g of 3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour,2-amino-6-methyl-4-(3-nitro-6-chlorophenyl)-l,4-dihydropyridine-3,5-dicarboxylicacid 3- ethyl ester S-methyl ester of melting point 124C (etha nol) isobtained. Yield: 73% of theory.

EXAMPLE 16 Upon boiling a solution of 10.4 g of2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoaceticacid ethyl ester in 100 ml of ethanol for 2 hours,2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,S-dicarboxylic aciddiethyl ester of melting point 183C (isopropanol) is obtained. Yield:78% of theory.

EXAMPLE 17 Upon boiling a solution of 14.0 g of benzylidenebenzoylaceticacid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 mlof ethanol for 2 hours, 2 amino-4,6-diphenyl- 1 ,4-dihydropyridine-3,S-dicarboxylic acid ethyl ester of melting point 183C (ethanol) isobtained. Yield: 48% of theory.

EXAMPLE 18 Upon heating a solution of 15.6 g of ethylideneacetoaceticacid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 mlof ethanol for 2 hours, 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point C (isopropanol) isobtained. Yield: 59% of theory.

EXAMPLE 19 Upon boiling a solution of 2.8 g of acetaldehyde, 5.6 g ofcyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 2 hours, 2- amino-4-methyl- 1 ,4,5,6,7,8hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 236C (ethanol) is obtained. Yield: 53% of theory.

EXAMPLE 20 Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.6g of cyclohexane-1,3-dione and 6.5 g of 11 amidinoacetic acid ethylester for 1 hour, 2-amino-4- (3-nitrophenyl l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 260C is obtained (alcohol/DMF). Yield: 61% of theory.

EXAMPLE 2 1 Upon boiling a solution of 7.1 g of 3-chlorobenzaldehyde,5.6 g of cyclohexane- 1 ,3-dione and 6.5 g of amidinoacetic acid ethylester in 150 ml of ethanol for 2 hours, 2-amino-4-( 3-chlorophenyl)- 1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 266C (ethanol/DMF is obtained. Yield: 66% of theory.

EXAMPLE 22 Upon boiling a solution of 5.3 g of pyridin-2-aldehyde, 5.6 gof cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in150 ml of alcohol for 3 hours,2-amino-4-(oz-pyridyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 260C isobtained (alcohol). Yield: 46% of theory.

EXAMPLE 23 Upon heating a solution of 7.6 g of 2-nitrobenzaldehyde, 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 2 hours,2-amino-4-(2-nitrophenyl)-l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 212C (alcohol) is obtained. Yield: 69%of theory.

EXAMPLE 24 EXAMPLE 25 Upon boiling a solution of 5.7 g of5,6-dimethoxypyrimidin-S-aldehyde, 3.8 g of cyclohexane-1,3-dione and4.4 g of amidinoacetic acid ethyl ester in 80 ml of ethanol for 8 hours,2-amino-4-(4,6-dimethoxypyrimid-5-y1)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 273C (alcohol) is obtained. Yield: 65% of theory.

EXAMPLE 26 Upon boiling a solution of 6.3 g of l-naphthaldehyde, 4.5 gof cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethyl ester in150 ml of ethanol for 2 hours, 2-amino-4-( naphthl -yl l,4,5,6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 279C (ethanol/DMF is obtained. Yield: 64% of theory.

EXAMPLE 27 Upon heating a solution of 6.3 g of isoquinolin-laldehyde,4.5 g of cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethylester in 100 ml of ethanol for 2 hours,2-amino-4-(isoquinol-1-yl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 272C (ethanol) is obtained.

EXAMPLE 28 Upon heating a solution of 4.8 g of 6-methylpyridin- 42-aldehyde, 4.5 of cyclohexane1,3-dione and 5.2 g of amidinoacetic acidethyl ester in ml of ethanol for 8 hours, 2-amino-4-(6-methylpyrid-2-yl)l,4,5,6,7,8-

hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point260C (ethanol/DMF) is ob tained. Yield: 46% of theory.

EXAMPLE 29 Upon boiling a solution of 13.3 g of3-nitrobenzylideneacetoacetic acid ethyl ester and 5.1 g ofamidinoacetamide in ml of ethanol for 2 hours, 2-amino-6-methyl-5-carbethoxy-4-( 3-nitrophenyl 1 ,4-dihydropyridine-3-carboxylic acid amide of melting point 260C (alcohol)is obtained. Yield: 52% of theory.

EXAMPLE 30 Upon heating a solution of 6.5 g of 2-cyanobenzaldehyde, 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 5 hours,2-amino-4-(2-eyanophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxy1icacid ethyl ester of melting point C (ethanol) is obtained. Yield: 49% oftheory.

EXAMPLE 31 Upon heating a solution of 26.3 g of3-nitrobenzylideneacetoacetic acid ethyl ester and 14.4 g ofamidinoacetic acid isopropyl ester in 250 ml of ethanol for 2 hours,2-amino-6-methyl-4-(3-nitrophenyl)-l,4-clihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester 5-ethyl esterof melting point l76C (ethanol) is obtained. Yield: 77% of theory.

EXAMPLE 32 Heating a solution of 14.3 g of2-trifluoromethylbenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 150 ml of ethanol for 1 houryields 2-amino-6-methyl-4-(2-trifluoromethylphenyl )-l,4-dihydropyridine-3 ,S-dicarboxylic acid 3-isopropyl ester 5-ethylester of melting point 106C. Yield 49% of theory.

EXAMPLE 33 Upon heating a solution of 13.9 g of3-nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in ml of ethanol for 1 hour,2-amino-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylic acid diisopropyl ester of melting point 122C (ether) isobtained. Yield: 62% of theory.

EXAMPLE 34 Upon boiling a solution of 12.2 g of2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 200 ml of ethanol for 1 hour,2-amino-6-methyl-4-(2-cyanophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester S-ethyl ester of melting point 200C (isopropanol)is obtained. Yield: 58% of theory.

EXAMPLE 35 Upon heating a solution of 12.5 g of3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 150 ml of ethanol 13 for 2 hours,2-amino-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester S-methyl ester of melting point 167C (ethano1) isobtained. Yield: 82% of theory.

EXAMPLE 36 EXAMPLE 37 Heating a solution of 13.2 g of3-nitrobenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 200 ml of ethanol for 2 hoursyields 2-amino-6-methyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxy1ic acid 3-n-propyl ester -ethyl esterof melting point 168C (ethanol). Yield: 79% of theory.

EXAMPLE 38 Boiling a solution of 8.5 g of o-nitroveratraldehyde,

4.0 g of cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethylester in 150 ml of ethanol fof 1 hour yields2-amino-4-(2-nitro-4,5-dimethoxyphenyl)- 1,4,5 ,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 261C (ethanol). Yield: 52% of theory.

EXAMPLE 39 Boiling a solution of 13.2 g of 3-nitrobenzylideneacetoaceticacid ethyl ester and 8.0 of amidinoacetic acid B-methoxyethyl esterin200 ml of ethanol for 2 hours yields2-amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine3,5 dicarboxylicacid 3- (B-methoxyethyl) ester 5-ethyl ester of melting point 174C.Yield: 59% of theory.

EXAMPLE 40 Upon heating a solution of 6.1 g of biphenyl-Z-aldehyde, 3.8g of cyclohexane-l,3dione and 5.1 g of amidinoacetic acid ethyl ester in100 ml of ethanol for 1 hour,2-amino-4-(biphenyl-Z-yU-l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylicacid ethyl ester of melting point 248C (ethanol) is obtained. Yield: 45%of theory.

l EXAMPLE 41 Boiling a solution of 13.4 g of l-naphthylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 8 hours yields 2amin0-6methyl4-( l-naphthyl l,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point174C (ethanol). Yield: 62% of theory.

EXAMPLE 42 Upon heating a solution of 11.5 g of2-cyanobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 100 ml of ethanol for 6 hours,2-amino-6-methyl-4-(2-cyanophenyl)-1,4- dihydropyridine-B,S-dicarboxylicacid 3-isopropyl ester S-methyl ester of melting point 21 1C (ethanol)is obtained. Yield: 72% of theory.

EXAMPLE 43 Upon boiling a solution of 11.5 g of2-cyanobenzylideneacetoacetic acid methyl ester and 6.5 g ofamidinoacetic acid ethyl ester in ml of ethanol for 8 hours,2-amino'6-methyl-4-(2-cyanophenyl )-l ,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester ofmelting point 224C (ethanol) is obtained. Yield: 66% of theory.

EXAMPLE 44 Upon boiling a solution of 14.8 g ofZ-phenylbenzylideneacetoacetic acid ethyl ester and 6.5 g ofamidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methy1- l -(biphenyl-2-yl 1,4-dihydropyridine-S,5-dicarboxylic acid ethyl ester of melting point182C (ethanol) is obtained. Yield 41% of theory.

EXAMPLE 45 Upon heating a solution of 12.5 g of3-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours,2-amino-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester S-methyl ester of melting point C (ethanol) isobtained. Yield 69% of theory.

EXAMPLE 46 Upon heating a solution of 12.2 g of (2-thenylidene)-acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 4 hours, 2- amino-6-methyl-4-( 2-thenyl l,4-dihydropyridine-3 ,5- dicarboxylic acid diethyl ester of meltingpoint C (ethanol) is obtained. Yield: 73% of theory.

EXAMPLE 47 Upon heating a solution of 10.9 g of benzylideneacetoaceticacid dimethylamide and'5.0 g of amidinoacetamide in .100 ml of ethanolfor 8 hours, 2-amino-6-methyl-4-phenyl-5-(N,N-dimethylaminocarbonyl)-l,4-dihydropyridine-3-carboxylicacid amide of melting point 236C (ethanol) :is obtained. Yield: 50% oftheory. 1

EXAMPLE 48 Heating a solution of 10.9 g of benzylideneacetoacetic aciddimethylamide and 6.5 g of amidinoacetic acid ethyl ester in 100 ml ofmethanol for 6 hours yields 2-amino-6-methyl-4-phenyll,4-dihydropyridine-3 ,5- dicarboxylic acid 3-ethyl ester5-(n,N-dimethylamide) of melting point 230C (alcohol). Yield: 61% oftheory.

EXAMPLE 49 Boiling a solution of 13.2 g of 2nitrobenzylideneacetoaceticacid ethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100ml of ethanol for 6 hours yields 2-amino-6-methyl-4-(2-nitrophenyll,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-ethylester of melting pont 139C (isopropanol). Yield: 39% of theory.

EXAMPLE. 5O

Boiling a solution of 13.2 g of 2-nitrobenzylideneacetoacetic acid ethylester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanolfor 6 hours yields 2-amino-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxy1ic acid diethyl ester of melting point159C (ethanol). Yield: 52% of theory.

EXAMPLE 5 1 Upon heating a solution of 12.5 g of2-nitrobenzylideneacetoacetic acid methyl ester and 7.2 g ofamidinoacetic acid isopropyl ester in 100 ml of ethanol for 8 hours,2-amine-6-methyl-4-(2-nitrophenyl)-l,4- dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester S-methyl ester of melting point 203C(isopropanol) is obtained. Yield: 50% of theory.

EXAMPLE 52 Upon heating a solution of 12.2 g of2-cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 8 hours,2-amino-6-methyl-4-(2-cyanophenyl)-1,4- dihydropyridine3,S-dicarboxylicacid 3-n-propyl ester 5-ethyl ester of melting point 182C (ethanol) isobtained. Yield: 62% of theory.

EXAMPLE 53 Upon heating a solution of 13.9 g of3-nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g ofamidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours,2-amino-6-methyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylicacid 3-n-propyl ester 5-isopropyl ester of melting-point 199C(isopropanol) is obtained. Yield: 75% of theory.

EXAMPLE 54 Heating a solution of 6.5 g of 3-cyanobenzaldehyde, 5.6 g ofcyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100ml of ethanol for 6 hours yields 2-amino-4-( 3-cyanophenyl)- 1 ,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of meltingpoint 262C (ethanol/dimethylfonnamide). Yield: 56% of theory.

EXAMPLE 55 Upon heating a solution of 93 g of 3-bromobenzaldehyde, 5.6 gof cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in100 ml of ethanol for 8 hours, 2-amino-4-(3-bromophenyl)-l,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 255C (ethanol) is obtained. Yield: 44% of theory.

EXAMPLE 56 Upon boiling a solution of 9.3 g of 2-bromobenzaldehyde, 5.6g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 6 hours, 2-amino-4-( 2'-bromophenyl )-1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 245C (ethanol) is obtained. Yield: 46% of theory.

EXAMPLE 57 Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde,5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethylester in ml of ethanol for 4 hours,2-amino-4-(3-carbethoxyphenyl)-1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point234C (ethanol) is obtained. Yield: 54% of theory.

EXAMPLE 58 Upon heating a solution of 7.4 g of 2-azidobenzaldehyde, 5.6g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl esterin 100 ml of ethanol for 4 hours, 2-amino-4-( 2-azidophenyl)-1,4,5,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester ofmelting point 209C (ethanol) is obtained. Yield: 58% of theory.

What is claimed is: 1. A compound of the formula:

R' NH:

wherein R is hydrogen; lower alkyl; alkenyl alkenyl of two to fourcarbon atoms; alkynyl of two to four carbon atoms; phenyl; phenylsubstituted by lower alkyl, lower alkoxy, halogeno, nitro, cyano,trifluoromethyl, azido, carbo(lower alkoxy), lower alkylsulfonyl, loweralkylsulfinyl, lower alkylthio, phenyl, di-methoxy, tri-methoxy, nitroand chloro, trifluoromethyl and nitro, nitro and methoxy, cyano andmethyl, nitro and di-methoxy or di-methoxy and bromo; or naphthyl;

R is hydrogen, lower alkyl, phenyl or pyridyl;

R is lower alkyl; and

R is lower alkyl.

2. A compound according to claim 1 wherein R is lower alkyl or phenyl.

3. A compound according to claim 2 wherein R is lower alkyl, naphthyl,phenyl or phenyl substituted by lower alkyl, lower alkoxy, halogeno,nitro, cyano, trifluoromethyl, azido, carbo(1ower alkoxy), loweralkylsulfonyl, lower alkylsulfinyl, lower alkylthio, phenyl, di-methoxy,tri-methoxy,- nitro and chloro, trifluoromethyl and nitro, nitro andmethoxy, cyano and methyl, nitro and di-methoxy or di-methoxy and bromo.

4. A compound according to claim 1 wherein R is hydrogen or lower alkyl.

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 whereinR1 is lower alkyl or phenyl.
 3. A compound according to claim 2 whereinR is lower alkyl, naphthyl, phenyl or phenyl substituted by lower alkyl,lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido,carbo(lower alkoxy), lower alkylsulfonyl, lower alkylsulfinyl, loweralkylthio, phenyl, di-methoxy, tri-methoxy, nitro and chloro,trifluoromethyl and nitro, nitro and methoxy, cyano and methyl, nitroand di-methoxy or di-methoxy and bromo.
 4. A compound according to claim1 wherein R1 is hydrogen or lower alkyl.